Abstract Twinstudiessuggestthatapproximately50%ofthevulnerabilitytococaineusedisorderisdeterminedby geneticfactors,butgenome-wideassociationstudies(GWAS)inhumanshaveonlybeguntoidentifyspecific genesthatconferthisrisk.Onemajorimpedimenttostudiesofcocaineusedisorderisthecomplexityofthe phenotypeandthelackofcontrolofenvironmentalvariables.Weproposeacomplementaryapproachthat leveragesamultidisciplinary,highlycollaborativeconsortiumthatcombinesnext-generationsequencingwith state-of-the-artbehavioralscreeninginaunique,geneticallydiverse,nonhumananimalmodel.Theprimary goalofthisproposalistoidentifygenevariantsthatareassociatedwithincreasedvulnerabilitytocompulsive cocaineusebyperformingaGWASinN/NIHheterogeneousstockrats.Wewillusethemostrelevantanimal modelofcocaineusedisorder(i.e.,escalationofintravenouscocaineself-administration)andhighly standardizedmeasuresofcontrolledandcompulsivecocaineself-administration.Toincreasetheimpactof thesefindingsandfacilitatetranslationalandbasicresearchstudiesonthemechanismsunderlyingcompulsive cocaineuse,wewillalsoestablishadata/tissuerepository(CocaineBioBank.org)frombehaviorallyand geneticallycharacterizedanimalsthatwillallowresearcherstofurtherinvestigatethecellularandmolecular mechanismsunderlyingcompulsivecocaineuseandidentifythebiologicalchangesassociatedwiththe expressionofspecificgenevariants.Thisprojectislikelytohaveasustainedandpowerfulimpactonthefield becauseitwill(1)characterizethetransitionfromcontrolledtocompulsivecocaineuseinmaleandfemale outbredrats,(2)identifygenesassociatedwithcompulsivecocaineuse,(3)createtheCocainBioBankwhich willprovidefreeaccesstobrain,kidney,liver,spleen,ovary,testis,adrenal,andbloodsampleswithavariety oftissuepreservationprotocolsthatwillallowthegenerationofinducedpluripotentstemcellsaswellas neuroanatomical,molecular,biochemical,andpharmacologicalstudiesonbehaviorally/genetically characterizedanimals.